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Release date:2024/12/25 19:33:17

Eli Lilly and Company recently announced that the U.S. Food and Drug Administration (FDA) has approved its blockbuster drug, Zepbound (tirzepatide), for treating moderate to severe obstructive sleep apnea (OSA) in adults with obesity. The new indication is for use in combination with reduced-calorie diet and increased physical activity.  Clinical trials revealed that up to 50% of patients no longer experienced OSA-related symptoms after one year of treatment with Zepbound. According to the press release, Zepbound is the first FDA-approved prescription medication specifically designed to treat obese adults with moderate to severe OSA.

Tirzepatide

Figure 1. Structure of tirzepatide

Obstructive sleep apnea (OSA) is a respiratory disorder characterized by episodes of breathing cessation or shallow breathing in sleep. This condition occurs when the muscles of the throat and tongue relax during sleep, leading to airway obstruction and restricted airflow, which disrupts normal breathing. OSA is most common in individuals who are obese or middle-aged and older. It is associated with serious complications, including coronary artery disease, heart failure, arrhythmias, and diabetes. Clinically, OSA symptoms include loud snoring, episodes of choking or gasping during sleep, and waking up feeling breathless. In severe cases, it can lead to cognitive decline and behavioral abnormalities.

This approval was primarily based on the results of the Phase 3 SURMOUNT-OSA clinical trial, which evaluated the efficacy of Zepbound (10 mg or 15 mg) in treating moderate to severe OSA in obese patients, regardless of whether they used positive airway pressure (PAP) therapy.

The analysis showed that among adults not using PAP therapy, Zepbound was about five times more effective than placebo in reducing breathing disruptions , leading to 25 fewer breathing disruptions per hour with Zepbound and five with placebo. Among adults using PAP therapy, Zepbound led to 29 fewer breathing disruptions per hour compared to six with placebo.

SURMOUNT-OSA

Figure 2. SURMOUNT-OSA results [1]

After one year, 42% of adults on Zepbound and 50% of adults on Zepbound with PAP therapy experienced remission or mild, non-symptomatic OSA, compared to 16% and 14% on placebo, respectively.

In addition to improving OSA symptoms, adults treated with Zepbound experienced significant weight loss, averaging 45 lbs (18%), while adults on Zepbound with PAP therapy lost an average of 50 lbs (20%). By comparison, weight loss in the placebo group was minimal, averaging 4 lbs (2%) and 6 lbs (2%), respectively.

The overall safety profile of Zepbound in the SURMOUNT-OSA study was consistent with previous clinical trials. The most commonly reported adverse events were gastrointestinal-related and generally mild to moderate in severity.

According to a 2018 study published in the Journal of Sleep Research, an estimated 936 million adults worldwide suffer from OSA. The global OSA drug market was valued at $9.2 billion in 2021 and is expected to grow at a compound annual rate (CAGR) of 4% from 2022 to 2028. Despite the increasing prevalence of OSA, treatment options have seen little progress over the past 40 years, relying primarily on non-drug interventions. Many patients use PAP devices during sleep to maintain airflow, but these methods offer limited effectiveness, and the discomfort of wearing the devices makes them difficult for many to tolerate.

Tirzepatide marks a significant breakthrough as the first FDA-approved medication specifically designed to treat OSA. This approval ends decades of limited therapeutic advancements and ushers in a new era for managing this condition.

About Tirzepatide

Tirzepatide, the world’s first GLP-1/GIP dual receptor agonist, has been approved for treating diabetes and promoting weight loss. Global sales data reveals that in the first three quarters of 2024, tirzepatide’s weight-loss version (Zepbound) generated $3.018 billion in revenue, while its diabetes treatment version (Mounjaro) earned $8.01 billion. Combined, these two products contributed $11.028 billion, accounting for approximately 34% of Eli Lilly’s total revenue during this period.

Tirzepatide’s therapeutic applications have expanded beyond diabetes and weight management to include respiratory diseases. In addition to its approvals for diabetes, weight loss, and the newly added OSA treatment, tirzepatide is now targeting a significant unmet need in cardiovascular health: heart failure. In November, Eli Lilly submitted a regulatory application for tirzepatide to treat heart failure with preserved ejection fraction (HFpEF) in obese patients.

Beyond these advancements, tirzepatide is being investigated for a wide range of conditions, including plaque psoriasis (PSO), nonalcoholic steatohepatitis (NASH), chronic kidney disease (CKD), and obesity-related morbidity and mortality (MMO). Over 140 clinical studies are currently underway to explore its potential across these areas.

Tirzepatide Combination Therapy for Weight Management 

As the use of GLP-1 weight loss drugs grows, their significant limitations are becoming more apparent. According to research, data from trials like STEP 1 and SUSTAIN 8 indicates that approximately 40% of the weight lost by patients taking semaglutide can be attributed to lean mass, primarily muscle tissue, raising concerns about potential cardiovascular and bone health risks due to muscle loss. This issue is also observed with tirzepatide, emphasizing the need for new therapies that can promote fat loss while preserving or even building muscle mass.

Eli Lilly is actively exploring or partnering on solutions for this challenge, including Bimagrumab from Versanis Pharmaceuticals and LAE102 from Laekna. Bimagrumab is a dual-specific anti-ActRIIA/ActRIIB antibody, and in October, Eli Lilly launched a Phase II clinical trial to evaluate the combination of Bimagrumab and tirzepatide for fat loss and muscle gain. LAE102 is an antibody targeting ActRIIA, and Eli Lilly’s recent collaboration in November with Laekna focuses on its potential.

Drugs that target ActRII can simultaneously inhibit fat accumulation and promote muscle growth because by blocking the signaling pathway on this receptor, which is present in both muscle and fat cells, they effectively prevent the negative regulation of muscle growth while also influencing fat metabolism, leading to a combined effect of increased muscle mass and reduced fat storage.

Conclusion

Based on current forecasts, tirzepatide is projected to outsell semaglutide by 2029, potentially reaching sales of approximately $27 billion, making it the leading drug in the obesity and diabetes market. To achieve this, Eli Lilly is not only focusing on weight loss indications, but is also developing several indications across different therapeutic areas.

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References:
[1] FDA approves Zepbound® (tirzepatide) as the first and only prescription medicine for moderate-to-severe obstructive sleep apnea in adults with obesity https://investor.lilly.com/news-releases/news-release-details/fda-approves-zepboundr-tirzepatide-first-and-only-prescription  
[2] Lilly reports Q3 2024 financial results highlighted by strong volume-driven revenue growth from New Products https://investor.lilly.com/news-releases/news-release-details/lilly-reports-q3-2024-financial-results-highlighted-strong
[3]  Lilly Partners With Chinese Biotech to Advance Muscle-Sparing Obesity Treatment https://www.biospace.com/business/lilly-partners-with-chinese-biotech-to-advance-muscle-sparing-obesity-treatment

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